合成路线:The intermediate 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (V) has been obtained as follows: The cyclization of 2-aminopyridine (I) with 3-acetyltetrahydrofuran-2-one (II) by means of polyphosphoric acid (PPA) at 160 C gives 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (III),which is hydrogenated with H2 over Pd/C in ethanol/water to yield the tetrahydro derivative (IV).Finally,the OH group of (IV) is treated with SOCl2 in dichloromethane to afford the target 2-chloroethyl intermediate (V).
合成路线:The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII),which is treated with SOCl2 to yield the corresponding acyl chloride (IX).The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI),which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII).The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII),which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV).Finally,this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.
参考文献标题:Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one
文献作者:Dalmases Barjoan,P.; Bosch Rovira,A.; Marquillas Olondriz,F.; Caldero Ges,J.M.(Vita-Invest,SA)
参考来源:ES 2050069
合成路线:The intermediate 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (IV) has been obtained as follows: The condensation of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (I) with dibenzylamine (II) by means of NaHCO3 in refluxing acetonitrile gives the tertiary amine (III),which is debenzylated by hydrogenation with H2 over Pd/C in warm ethanol to afford the target intermediate (IV).
合成路线:The condensation of tetrahydropyran-4-carbonyl chloride (V) with refluxing 1,3-difluorobenzene (VI) by means of AlCl3 gives 1-(2,4-difluorophenyl)-1-(tetrahydropyran-4-yl)methanone (VII),which is treated with hydroxylamine hydrochloride and sodium acetate in refluxing ethanol/water to yield the corresponding oxime (VIII).The cyclization of (VIII) by means of KOH in refluxing methanol affords 6-fluoro-3-(tetrahydropyran-4-yl)-1,2-benzisoxazole (IX),which is treated with NaI and Ac-Cl and then with K2CO3 in refluxing acetonitrile to provide the 5-iodopentanol derivative (X).The reaction of the OH group of (X) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XI),which is finally cyclized with the intermediate amine (IV) by means of NaHCO3 in refluxing acetonitrile to yield the target piperidine.
参考文献标题:Process for obtaining 3-2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine-4-one
文献作者:Huguet-Clotet,J.; Marquillas Olondriz,F.; Caldero Ges,J.M.; Del Castillo Nieto,J.C.; Dalmases Barjoan,P.; Bosch Rovira,A.(Vita-Invest,SA)
参考来源:ES 2074966
合成路线:The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III),which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV).The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V),which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI).Finally,this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.
参考文献标题:Preparation of risperidone
文献作者:Diller,D.; Krochmal,B.; Dolitzky,B.-Z.; Aronhime,J.(Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA,Inc.)
参考来源:WO 0212200; WO 0214286
合成路线:The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III),which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV).The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V),which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI).Finally,this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.
参考文献标题:Risperidone
文献作者:Castar,J.; Prous,J.
参考来源:Drugs Fut 1988,13(12),1052
产品链接: CAS No. 106266-06-2››